1736
Vol. 56, No. 12
generally proceeds under acidic conditions, the present reac- readily applicable to various kinds of carboxylic acids.
tion proceeds under basic conditions. Thus, the Boc group,
Experimental
which is subject to decomposition under acidic conditions, is
compatible with our reaction conditions (Run 7).
General Procedure for Preparation of 2-Oxazoline from Carboxylic
Acid: 2-(2-Phenethyl)-2-oxazoline 3a18) DMT-MM (111 mg, 0.40 mmol)
was added at room temperature to a solution of 3-phenylpropionic acid 1a
(50.0 mg, 0.33 mmol), 2-bromoethylammonium bromide 2 (XꢀBr) (81.9
mg, 0.40 mmol), and NMM (40.4 mg, 0.40 mmol) in methanol (3 ml). After
stirring for 1 h, a methanol solution of KOH (1 M, 1.40 ml, 1.40 mmol) was
added, and the resulting mixture was refluxed for 1.5 h. The reaction mixture
was poured into water and extracted with ether. The organic phase was com-
bined and washed successively with 1 M HCl, NaHCO3, and brine, and then
dried over MgSO4. The crude product was purified by alumina column chro-
matography (Neutral, super V) to give 2-(2-phenethyl)-2-oxazoline (3a)
Chiral oxazolines are utilized as chiral metal ligands, such
as C2-symmetric chiral bis(oxazolines), as well as a chiral
auxiliaries.15) We succeeded in synthesizing chiral oxazolines
6 from chiral 2-chloroethylammonium salts 5, which were
readily prepared from chiral aminoethanols (Table 3).16)
When the reaction performed from N-Cbz-L-phenylalanine
and (S)-1-chloro-2-aminopropane hydrochloride, a trace
amount of the diastereomer (ꢁ1%) resulting from racemiza-
tion at the asymmetric a-carbon was observed by NMR
analysis (Chart 2).17) A similar result was observed with
N-Boc-L-phenylalanine and (S)-1-chloro-2-aminopropane
hydrochloride (yield 77%, racemization ꢁ1%).
(42.3 mg) in 73% yield. Pale yellow oil; IR (neat) 2952, 1668 cmꢂ1 1H-
;
NMR (CDCl3) d: 2.55—2.62 (m, 2H), 2.93—3.00 (m, 2H), 3.79—3.87 (m,
2H), 4.20—4.27 (m, 2H), 7.17—7.24 (m, 3H), 7.26—7.32 (m, 2H); HR-MS
Calcd for C11H13NO (Mꢃ) 175.0997, Found 175.0997.
2-Phenyl-2-oxazoline (3b)19): Pale yellow oil; IR (neat) 2930, 1650 cmꢂ1
;
1H-NMR (CDCl3) d: 4.06 (t, Jꢀ9.5 Hz, 2H), 4.43 (t, Jꢀ9.5 Hz, 2H), 7.38—
7.50 (m, 3H), 7.92—7.98 (m, 2H); HR-MS Calcd for C9H9NO (Mꢃ)
147.0684, Found 147.0686.
In summary, we present a simple one-pot method for the
synthesis of 2-oxazolines by using DMT-MM, which in-
volves dehydrocondensation of carboxylic acids and 2-
2-(1-Phenethyl)-2-oxazoline (3c)20): Pale yellow oil; IR (neat) 2977,
haloethylammonium salts followed by base-promoted ring 1663 cmꢂ1; 1H-NMR (CDCl3) d: 1.55 (d, Jꢀ7.2 Hz, 3H), 3.74 (q, Jꢀ7.2 Hz,
1H), 3.82—3.89 (m, 2H), 4.15—4.27 (m, 2H), 7.22—7.36 (m, 5H); HR-MS
closure of the resulting b-haloethylamide. The reaction is
Calcd for C11H13NO (Mꢃ) 175.0997, Found 175.0997.
2-(3-Butenyl)-2-oxazoline (3d)21)
:
Colorless oil; IR (neat) 2979,
1667 cmꢂ1
;
1H-NMR (CDCl3) d: 2.33—2.44 (m, 4H), 3.82 (t, Jꢀ9.5 Hz,
Table 2. Synthesis of 2-Alkyloxazolines from Carboxylic Acids by the
One-Pot Procedure
2H), 4.22 (t, Jꢀ9.5 Hz, 2H), 4.97—5.12 (m, 2H), 5.78—5.92 (m, 1H); ESI-
MS m/z: 126 [(MꢃH)ꢃ].
2-(trans-2-Phenylethenyl)-2-oxazoline (3e)22): Pale yellow oil; IR (neat)
3024, 2928, 1653 cmꢂ1; 1H-NMR (CDCl3) d: 3.99 (t, Jꢀ9.3 Hz, 2H), 4.35 (t,
Jꢀ9.3 Hz, 2H), 6.64 (d, Jꢀ16.3 Hz, 1H), 7.30—7.41 (m, 4H), 7.45—7.52
(m, 2H); HR-MS Calcd for C11H11NO (Mꢃ) 173.0841, Found 173.0839.
2-Cyclohexyl-2-oxazoline (3f)23)
: Pale yellow oil; IR (neat) 2931,
1662 cmꢂ1; H-NMR (CDCl3) d: 1.15—1.49 (m, 5H), 1.60—1.81 (m, 3H),
1.88—1.97 (m, 2H), 2.24—2.34 (m, 1H), 3.81 (t, Jꢀ9.3 Hz, 2H), 4.20 (t, Jꢀ
9.3 Hz, 2H); HR-MS Calcd for C9H15NO (Mꢃ) 153.1154, Found 153.1158.
2-(N-Boc-1-amino-2-phenylethyl)-2-oxazoline (3g)24): Pale yellow oil; IR
(neat) 3357, 1691, 1665 cmꢂ1; 1H-NMR (CDCl3) d: 1.41 (s, 9H), 2.95—3.20
(m, 2H), 3.70—3.86 (m, 2H), 4.23—4.35 (m, 2H), 4.65 (br s, 1H), 5.15 (br s,
1H), 7.14 (d, Jꢀ6.8 Hz, 2H), 7.19—7.30 (m, 3H); ESI-MS m/z: 291 [(Mꢃ
H)ꢃ], 313 [(MꢃNa)ꢃ].
Refluxing Yield
time (h)
1
Run Carboxylic acid
X
Product
(%)a)
1
2
3
PhCOOH
1b
1c
Br
Cl
Br
3b
3b
3c
3.5
4.0
3.0
83
58
70
4
5
6
7
1d
1e
1f
Br
Br
Br
Br
3d
3e
3f
1.5
2.5
1.5
1.0
100b)
74
(S)-2-(2-Phenylethyl)-4-methyl-2-oxazoline: Pale yellow oil; [a]D22 ꢂ31.8
(cꢀ0.22, CHCl3); IR (neat) 2967, 1669 cmꢂ1; H-NMR (CDCl3) d: 1.22 (d,
1
62
Jꢀ6.6 Hz, 3H), 2.55—2.60 (m, 2H), 2.91—3.00 (m, 2H), 3.75 (t, Jꢀ7.9 Hz,
1H), 4.09—4.20 (m, 1H), 4.32 (dd, Jꢀ8.0, 9.3 Hz, 1H), 7.17—7.32 (m, 5H);
HR-MS Calcd for C12H15NO (Mꢃ) 189.1154, Found 189.1146.
1g
3g
83
(S)-2-(2-Phenylethyl)-4-phenylmethyl-2-oxazoline25): Pale yellow oil; [a]D22
a) Isolated yield. b) Determined by GC.
ꢂ10.6 (cꢀ0.73, CHCl3); IR (neat) 3026, 2927, 1668 cmꢂ1 1H-NMR
;
(CDCl3) d: 2.54—2.64 (m, 3H), 2.95 (t, Jꢀ7.6 Hz, 2H), 3.05 (dd, Jꢀ5.2,
13.7 Hz, 1H), 3.94 (dd, Jꢀ7.1, 7.7 Hz, 1H), 4.15 (dd, Jꢀ8.5, 8.5 Hz, 1H),
4.31—4.41 (m, 1H), 7.15—7.32 (m, 10H); HR-MS Calcd for C18H19NO
(Mꢃ) 265.1467, Found 265.1479.
Table 3. Synthesis of Chiral Oxazolines
(S)-2-(2-Phenylethyl)-4-iso-propyl-2-oxazoline26): Pale yellow oil; [a]D22
ꢂ54.8 (cꢀ0.19, CHCl3); IR (neat) 3028, 2958, 1669 cmꢂ1 1H-NMR
;
(CDCl3) d: 0.84 (d, Jꢀ6.8 Hz, 3H), 0.92 (d, Jꢀ6.8 Hz, 3H), 1.64—1.77 (m,
1H), 2.59 (t, Jꢀ8.1 Hz, 2H), 2.95 (t, Jꢀ7.8 Hz, 2H), 3.83—3.96 (m, 2H),
4.16—4.25 (t, Jꢀ9.2 Hz, 1H), 7.15—7.32 (m, 5H); HR-MS Calcd for
C14H19NO (Mꢃ) 217.1467, Found 217.1464.
(S,S)-2-[N-(Benzyloxycarbonyl)-1-amino-2-phenylethyl]-4-methyl-2-oxa-
zoline: Pale yellow oil; 1H-NMR (CDCl3) d: 1.18 (d, Jꢀ5.4 Hz, 3H), 2.93—
3.22 (m, 2H), 3.82 (t, Jꢀ8.1 Hz, 1H), 3.99—4.17 (m, 1H), 4.36 (t, Jꢀ
8.1 Hz, 1H), 4.63—4.80 (m, 1H), 5.10 (dd, Jꢀ10.8, 16.2 Hz, 2H), 5.35 (d,
Run
R
Refluxing time (h)
Yield (%)a)
1
2
3
L-CH3
L-PhCH2
L-(CH3)2CH
2.0
2.0
2.5
81 (86b))
86
95
a) Isolated yield. b) Determined by GC.
Chart 2